Electrophilic Amide Allylation of 3-Heterosubstituted Oxindoles: A Route to Spirocyclic 2-Oxindoles Containing the α-Methylene-γ-butyrolactam Structure

Article abstract of DOI:10.1002/ejoc.201800084

This article reports a new route to access spirocyclic 2-oxindoles containing the α-methylene-γ-butyrolactam structure via “electrophilic amide allylation”. The key reaction was accomplished by using acetoxy methacrylamides and tetrakis(triphenylphosphine)palladium as catalyst, affording a variety of the amide allylated products in excellent yields. The successful cyclization of these products has demonstrated the potential utility of this approach to offer a practical synthesis of spirocyclic oxindoles.

Full text of DOI:10.1002/ejoc.201800084

A Journal of
Accepted Article
Title: Electrophilic amide allylation of 3-heterosubstituted oxindoles:
a new route to spirocyclic 2-oxindole containing α-methylene-γ-
butyrolactam structure
Authors: Tetsuya Sengoku, Daichi Hayashi, Masaki Takahashi, and
Hidemi Yoda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800084
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10.1002/ejoc.201800084
European Journal of Organic Chemistry
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Electrophilic amide allylation of 3-heterosubstituted oxindoles: a
new route to spirocyclic 2-oxindole containing α-methylene-γ-
butyrolactam structure
Tetsuya Sengoku,[a] Daichi Hayashi,[a] Masaki Takahashi[a] and Hidemi Yoda*[a]
Abstract: This article reports a new route to access spirocyclic 2-
oxindole containing α-methylene-γ-butyrolactam structure via
“electrophilic amide allylation”. The key reaction was accomplished
by
using
acetoxy
methacrylamides
and
tetrakis(triphenylphosphine)palladium as
a
catalyst, affording
a
variety of the amide allylated products in excellent yields. The
successful cyclization of these products has demonstrated the
potential utility of this approach to offer practical synthesis of
spirocyclic oxindoles.
Introduction
α-Methylene-γ-butyrolactone and lactam structures are
important molecular motifs due to the fact that they are often
found in potent bioactive compounds and thus useful for
developing pharmaceutical products.[1] For the construction of
these functional moieties, cyclization of γ-hydroxy/γ-amino
functionalized esters or their analogous compounds could be
envisioned as one of the most effective ways.[2,3] In this context,
we have established an efficient approach based on indium-
catalyzed nucleophilic addition of β-amido functionalized
allylstannanes A (see structure in Scheme 1a) to a range of
carbonyl compounds such as isatins[4] to afford γ-hydroxy
amides, which undergo acid-promoted cyclization to successfully
generate the α-methylene-γ-butyrolactones. Furthermore, we
achieved the enantioselective synthesis of these compounds by
the use of chiral ligand combined with indium catalyst.[5] The
utility of this "amide allylation" approach has been culminated in
the enantioselective synthesis of antineoplastic spirocyclic
oxindoles B[6] to demonstrate the extremely high levels of
stereocontrol (Scheme 1a).[7] In the course of our intensive
research work on the catalytic "amide allylation", we have also
developed a synthetic approach to α-methylene-γ-butyrolactams
by employing imine substrates.[8] However, attempts to extend
this strategy for preparing 3, a lactam analog of B, met with
failure because imino group of the substrate 1 was highly
susceptible to the indium catalyst and decomposed during the
reaction (Scheme 1b, 1 → 2a). In light of our previous results for
Scheme 1. Synthetic approaches for spirocyclic oxindoles containing α-
methylene-γ-butyrolactone and lactam structures.
obtaining α-methylene-γ-butyrolactams from the corresponding
acyclic precursors,[8] the key to successful synthesis of 3 was to
explore an alternative approach toward this synthetic
intermediate. Thus, our next challenge was to establish a
synthetic route on the basis of umpolung strategy, which would
be expected to allow for the synthesis of 2a from 3-Boc-
aminooxindole 4a and 2-acetoxymethyl acrylamide 5a under the
influence of palladium catalysts (Scheme 1c).[9,10] Here, we
report our successful efforts for the development of a new
strategy, which we named "electrophilic amide allylation", to
complement our previous synthetic approach.
Results and Discussion
The requisite reagent 5a was prepared by allylic oxidation of N-
phenyl methacrylamide by way of β-amido allylboronate[11] and
successive acetylation (67% yield for 2 steps). Then, we
examined the palladium-catalyzed reaction between 4a[12] and
5a in dichloromethane solution at room temperature. Our initial
attempt was made to carry out the reaction in the presence of
Pd(0) species in-situ generated from palladium acetate and
triethylamine, which afforded only a 16% yield of the amide
allylated product 2a (Table 1, entry 1). Next, we examined the
[a]
T. Sengoku, D. Hayashi, M. Takahashi, H. Yoda
Department of Applied Chemistry, Faculty of Engineering
Shizuoka University
3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561, Japan
E-mail: yoda.hidemi@shizuoka.ac.jp
https://wwp.shizuoka.ac.jp/lab-o-chem/
use of 10 mol
% of tris(dibenzylideneacetone)dipalladium
(Pd2(dba)3) instead of the Pd(0) species. In this case, however,
no reaction occurred and complete recovery of the starting
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800084
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Table 1. Screening of palladium reagents and solvents on the reaction of 4a
with 5a[a]
Entry
1
.
Pd catalyst [mol %]
solvent
CH2Cl2
time [h]
5
yield [%][b]
16
Pd(OAc)2 (10)
Et3N (20)
Table 2. Amide allylation of 3-heterosubstituted oxindoles.
entry
1
4 (R1, R2)
5 (R3)
time [h]
1
2
yield [%][a]
70
2
3
Pd2(dba)3 (10)
CH2Cl2
CH2Cl2
24
2
0
4a
(NHBoc,
5b (Ph)
2a
Pd2(dba)3 (10)
dppb (20)
78
Me)
2
3
4
5
6
7
4a
4a
4a
4a
4a
5c (Ph)
5d (p-anis)
5e (TBP)[b]
5f (Nap)[c]
5g (Et)
1
1
1
1
1
1
2a
2b
2c
2d
2e
2f
91
4
5
Pd(PPh3)4 (10)
CH2Cl2
DCE[c]
0.5
2
>99
>99
>99
99
Pd(OAc)2 (10)
PPh3 (40)
6
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (1)
MeCN
THF
0.5
1
96
97
7
95
98
8
CHCl3
toluene
EtOH
1
>99
>99
93
4b
Ph)
(NHBoc,
5a
>99
9
0.5
2
8
4c (NHBoc, H)
4d (OH, Me)
4e (OBoc, Me)
4f (SPh, Me)
4g (OH, H)
5a
5a
5a
5a
5a
5a
1
1
2
1
2
2
2g
2h
2i
94
10
11[d]
9
80 (91)[d]
42 (88)[d]
91
CH2Cl2
3
98
10
11
12
13
[a] Reactions of 4a with 5a (1.2 equiv.) were conducted at room temperature.
[b] Isolated yield of 2a. [c] The reaction was carried out in 1,2-dichloroethane
(DCE) at 40 °C. [d] The product could be synthesized on a gram scale (1.57
g of 2a).
2j
2k
2l
68[e]
4h (SPh, H)
83
[a] Isolated yield. [b] TBP: p-(tert-butyl)phenyl. [c] Nap: 1-naphthyl. [d] Yields
based on recovery of the starting materials. [e] 2k was obtained as a mixture
with a bisallylated derivative. The yield was calculated from 1H NMR spectrum
of the mixture.
materials was observed (Table 1, entry 2). Remarkably, we
found that addition of 1,4-bis(diphenylphosphino)butane (dppb),
which would serve as a common phosphine ligand, led to a
dramatic improvement of the reactivity; the reaction yield of 2a
was increased to as high as 78% (Table 1, entry 3). Furthermore,
other
phosphine-based
catalyst
such
as
tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) was shown to
facilitate this conversion, markedly shortening the reaction time
to 30 min to provide 2a in quantitative yield (Table 1, entry 4).
Evidently, this reaction was well reproduced, as demonstrated
Encouraged by the success of this approach, we next explored
the substrate scope by following the optimized procedure as
given in entry 4 of Table 1. Under the reaction conditions, O-Boc
and Bz-substituted reagents 5b,c were shown to undergo the
"electrophilic amide allylation" successfully to give 2a with
sufficiently high yields (Table 2, entries 1 and 2). Likewise, other
allylic reagents such as N-aryl and alkyl-substituted reagents 5d-
g also reacted with 4a to generate the respective products 2b-e
in excellent yields (>97%, see Table 2, entries 3-6). At the same
time, for other substrates such as N-phenyl and unsubstituted
variants 4b and 4c, the reactions still occurred efficiently to
produce 2f and 2g in very high yields of >99 and 94%,
respectively (Table 2, entries 7 and 8). Furthermore, it is
interesting to note that the catalysis showed adequate levels of
by
the
replacement
with
palladium
acetate
and
triphenylphosphine (Table 1, entry 5).[13] With these results in
hand, we turned our efforts to screening of solvents with the use
of Pd(PPh3)4 (Table 1, entries 6–10). To our delight, all the
solvents tested were well tolerated under the reaction conditions
to offer comparably high yields of 2a even in ethanol (Table 1,
entry 10). At this point, dichloromethane was identified as the
most effective solvent that solubilizes appreciable amount of the
substrates. This solubilization property makes the method
adaptable to gram-scale synthesis. Indeed, the reaction
performed at a high concentration (1.0 M) proceeded smoothly
to give a very high yield (98%) of the product only with a catalyst
loading as low as 1 mol % (Table 1, entry 11).
reactivity toward
a
broad range of 3-heterosubstituted
oxindoles,[14-17] even when catalyst-poisonous 3-phenylthio
derivative 4f,h[18] were used, thereby affording 2h-l with high
catalyst productivity (Table 2, entries 9–13).
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10.1002/ejoc.201800084
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At the final stage of the work, we undertook further efforts on
constructing the spirocyclic 2-oxindole structure by employing
the amide allylated products. As shown in Table 3, we attempted
to use all the homoallylic amines 2a-g for the cyclization.
Subjecting these materials to our previous synthetic conditions[7]
that involved reaction with Boc anhydride, spontaneous
cyclization induced by selective protection at the secondary
amide group occurred efficiently to yield N-Boc protected
spirocyclic lactams 6a-c in 93-99% yields.[19] The Boc group of
these compounds could be removed with no significant loss of
the structural integrity by exposure to trifluoroacetic acid, which
gave rise to deprotected product 3a-c in almost quantitative
yields (86-97% overall yields from 4).
Experimental Section
General methods: All solvents and reagents were of reagent grade
quality, and used without further purification unless otherwise stated.
Chloroform, acetonitrile, ethanol, toluene, dichloromethane and 1,2-
dichloroethane were dried over MS 4 Å or MS 3 Å prior to use,
respectively. Tetrahydrofuran was dried over Na wire under a nitrogen
atmosphere. The 1H and 13C nuclear magnetic resonance (NMR) spectra
operating at the frequencies of 300 and 75 MHz, respectively, on a JEOL
JNM-AL300 spectrometer were recorded in chloroform–d (CDCl3) unless
otherwise noted. Chemical shifts are reported in parts per million (ppm)
relative to TMS and the solvent used as internal standards, and the
coupling constants are reported in hertz (Hz). Reactions were monitored
by thin layer chromatography (TLC) using Merck TLC silica gel 60F254
,
visualized by irradiation with UV light and/or by treatment with
phosphomolybdic acid or p-anisaldehyde stain followed by heating.
Column chromatography was performed using silica gel 60N (spherical
neutral) from Kanto Chemical Co. and eluting with the indicated solvent
system. Fourier transform infrared (FTIR) spectra were recorded on a
JASCO FT/IR-550 spectrometer. Elemental analyses were performed by
JSL Model JM 10 instruments. 3-Heterosubstituted oxindoles 4a,d,e,g
and 4h, were prepared according to the literature procedure.[11-15]
Table 3. Transformation of allyl adducts 2a-g to spirocyclic oxindoles 3a-c.
Synthesis and characterization of 4b: To
a solution of N-
phenylisatin[21] (407 mg, 1.82 mmol) in ethanol (3.6 mL) were added
hydroxylamine hydrochloride (143 mg, 2.06 mmol) and water (2 drops) at
room temperature. After stirring the solution at the same temperature for
3 hours, the reaction mixture was diluted with water (2.0 mL). The
resulting mixture was extracted with ethyl acetate (10 mL×2). The
combined organic extracts were washed with brine (20 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a crude material
(437 mg) which was used in the next step without further purification. Rf =
0.51 (silica gel, hexane/EtOAc = 1/1).
Entry
2
time 1 [h]
24
6 [%][a]
6a (97)
6a (99)
6a (95)
6a (99)
6a (98)
6b (96)
6c (93)
time 2 [h]
3 [%][a]
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
24
3a (99)
12
-
-
12
-
-
24
-
-
24
-
-
To a solution of the crude material (437 mg) in methanol (3.6 mL) was
added 10% Pd/C (34.2 mg), and the heterogeneous mixture was stirred
under a hydrogen atmosphere at room temperature for 4 hours. The
reaction mixture was filtered with Celite and concentrated in vacuo to
provide a crude material (412 mg) which was used in the next step
without further purification. Rf = 0.16 (silica gel, hexane/EtOAc = 1/1).
12
24
24[c]
3b (99)
3c (98)
2g
12[b]
[a] Isolated yield. [b] Reaction was carried out with Boc2O (6.0 eq), Et3N (6.0
eq) and DMAP (0.5 eq). [c] Reaction was carried out with TFA (0.5 eq).
To a solution of the crude material (412 mg) in dichloromethane (6.1 mL)
was added di-tert-butyl dicarbonate (411 mg, 1.88 mmmol) under a
nitrogen atmosphere at room temperature. The mixture was stirred for 15
hours and concentrated in vacuo to provide a crude material. This
material was purified by column chromatography (silica gel,
hexane/EtOAc = 3/1) and recrystallization (hexane/EtOAc) to give 4b
(246 mg, 0.758 mmol, 42%) as a white solid. Rf = 0.42 (silica gel,
hexane/EtOAc = 2/1); m.p. 180–182 °C; IR (KBr) 3349 (N-H), 2978 (C–H),
1745 (C=O), 1685 (C=O) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.55-7.38
(m, 6H, ArH), 7.28-7.21 (m, 1H, ArH), 7.11 (t, J = 7.5 Hz, 1H, ArH), 6.81
(d, J = 7.5 Hz, 1H, ArH), 5.25 (s, 2H, CH, NH), 1.47 (s, 9H, CH3); 13C
NMR (75 MHz, CDCl3) δ 173.9 (C), 155.6 (C), 143.6 (C), 134.2 (C), 129.6
(CH), 129.0 (CH), 128.1 (CH), 126.7 (C), 126.4 (CH), 124.7 (C), 123.3
(CH), 109.5 (CH), 80.6 (C), 53.8 (CH), 28.2 (CH3). Anal. Calcd for
C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.31; H, 6.06; N, 8.69.
Conclusions
In conclusion, we have established a new synthetic route, based
on umpolung strategy using “electrophilic amide allylation”, to
achieve efficient synthesis of spirocyclic 2-oxindole containing α-
methylene-γ-butyrolactam structure.[20] The key reaction is
highlighted by the toleration of a wide range of functionalities
such as oxygen and sulfur substituents at the C3 position of 2-
oxindole. The success of transformation of the product into
spirocyclic oxindole has shown its potential utility to offer
significant advantages compared to our previous strategy for
constructing variously 3-heterosubstituted spirooxindole systems.
Further investigations on the enantioselective construction of
such functionalized heterocycles is underway in our laboratory.
Synthesis and characterization of 4c: To a solution of isatin (515 mg,
3.50 mmol) in ethanol (7.0 mL) were added hydroxylamine hydrochloride
(298 mg, 4.29 mmol) and water (2 drops) at room temperature. After
stirring the solution at the same temperature for 16 hours, the reaction
mixture was diluted with water (5.0 mL). The resulting mixture was
extracted with ethyl acetate (30 mL×2). The combined organic extracts
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10.1002/ejoc.201800084
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were washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to provide a crude material (553 mg) which was
used in the next step without further purification. Rf = 0.16 (silica gel,
hexane/EtOAc = 1/1).
26.2 (CH3). Anal. Calcd for C15H13NOS: C, 70.56; H, 5.13; N, 5.49.
Found: C, 70.64; H, 5.25; N, 5.65.
Synthesis and characterization of 5a: To
a solution of N-
phenylmethacrylamide (2.42 g, 15.0 mmol) and potassium tert-butoxide
(4.21 g, 37.5 mmol) in THF (150 mL) was added dropwise n-butyl lithium
(1.55 M in hexane, 22 mL, 34 mmol) at -78 °C under a nitrogen
atmosphere. After stirring the solution at the same temperature for 10
min, trimethyl borate (2.5 mL, 22 mmol) was added. After stirring the
solution at -78 °C for additional 10 min, 35% aqueous hydrogen peroxide
(6.0 mL) and 3.0 M aqueous sodium hydroxide (30 mL) were added. The
mixture was then warmed to room temperature and stirred for 9 hours.
The reaction was quenched by addition of saturated aqueous sodium
thiosulfate (50 mL), and the solvent was removed under reduced
pressure. The residue was extracted with ethyl acetate (80 mL). The
combined organic extracts were washed with brine (50 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a crude material.
This material was purified by column chromatography (silica gel,
hexane/EtOAc = 2/1 to 1/1) and recrystallization (hexane/EtOAc) to give
allylic alcohol I (1.91 g, 10.8 mmol, 72%) as a white solid. Rf = 0.23 (silica
gel, hexane/EtOAc = 1/1); m.p. 73–75 °C; IR (KBr) 3412 (N–H), 3304 (O–
H), 3058 (C–H), 1653 (C=O), 1624 (C=C) cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.88 (brs, 1H, NH), 7.53 (d, J = 7.5 Hz, 2H, ArH), 7.31 (t, J = 7.5
Hz, 2H, ArH), 7.11 (t, J = 7.5 Hz, 1H, ArH), 6.08 (s, 1H, CH2), 5.55 (s, 1H,
CH2), 4.40 (d, J = 2.4 Hz, 2H, CH2), 3.42 (brs, 1H, OH); 13C NMR (75
MHz, CDCl3) δ 165.5 (C), 141.7 (C), 137.5 (C), 128.9 (CH), 124.6 (CH),
123.6 (CH2), 120.4 (CH), 63.4 (CH2). Anal. Calcd for C10H11NO2: C,
67.78; H, 6.26; N, 7.90. Found: C, 67.61; H, 6.12; N, 8.03.
To a solution of the crude material (553 mg) in methanol (7.0 mL) was
added 10% Pd/C (61.2 mg), and the heterogeneous mixture was stirred
under a hydrogen atmosphere at room temperature for 18 hours. The
reaction mixture was filtered with Celite and concentrated in vacuo to
provide a crude material (524 mg) which was used in the next step
without further purification. Rf = 0.06 (silica gel, hexane/EtOAc = 1/2).
To a solution of the crude material (524 mg) in dichloromethane (18 mL)
was added di-tert-butyl dicarbonate (817 mg, 3.74 mmol) under a
nitrogen atmosphere at room temperature. The mixture was stirred for 5
hours and concentrated in vacuo to provide a crude material. This
material was purified by column chromatography (silica gel,
hexane/EtOAc = 2/1 to 1/1) and recrystallization (hexane/EtOAc) to give
4c (277 mg, 1.12 mmol, 32%) as a white solid. Rf = 0.23 (silica gel,
hexane/EtOAc = 1/1); m.p. 187–189 °C; IR (KBr) 3443 (N–H), 3276 (N–
H), 2986 (C–H), 2928 (C–H), 1748 (C=O), 1673 (C=O) cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.00 (brs, 1H, NH), 7.35 (d, J = 6.6 Hz, 1H, ArH),
7.27-7.22 (m, 1H, ArH), 7.05 (t, J = 7.5 Hz, 1H, ArH), 6.86 (d, J = 7.5 Hz,
1H, ArH), 5.19 (brs, 1H, CH), 5.10 (brs, 1H, NH), 1.46 (s, 9H, CH3); 13C
NMR (75 MHz, DMSO-d6, 50 ºC) δ 175.7 (C), 155.2 (C), 142.2 (C), 129.1
(C), 128.1 (CH), 123.3 (CH), 121.2 (CH), 109.2 (CH), 78.3 (C), 53.2 (CH),
27.9 (CH3). Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28.
Found: C, 62.82; H, 6.28; N, 11.16.
To a solution of I (460 mg, 2.60 mmol) in dichloromethane (5.2 mL) were
added acetic anhydride (331 mg, 3.24 mmol) and triethylamine (383 mg,
3.78 mmol) at room temperature under a nitrogen atmosphere. The
mixture was stirred at the same temperature for 18 hours and
concentrated in vacuo to provide a crude material. This material was
purified by column chromatography (silica gel, hexane/EtOAc = 3/1 to
2/1) and recrystallization (hexane/EtOAc) to give 5a (528 mg, 2.41 mmol,
93%) as a white solid. Rf = 0.32 (silica gel, hexane/EtOAc = 2/1); m.p.
97–99 °C; IR (KBr) 3387 (N–H), 1721 (C=O), 1673 (C=O), 1634 (C=C)
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.07 (brs, 1H, NH), 7.58 (d, J = 7.6 Hz,
2H, ArH), 7.35 (t, J = 7.6 Hz, 2H, ArH), 7.14 (m, 1H, ArH), 6.16 (s, 1H,
CH2), 5.77 (s, 1H, CH2), 4.93 (d, J = 0.9 Hz, 2H, CH2), 2.14 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3) δ 170.9 (C), 164.1 (C), 139.8 (C), 137.6 (C),
129.0 (CH), 124.6 (CH), 124.3 (CH2), 120.1 (CH), 63.3 (CH2), 20.9 (CH3).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.69;
H, 6.08; N, 6.29.
Synthesis and characterization of 4f: To a solution of 4d (295 mg, 1.81
mmol) in dichloromethane (3.6 mL) were added triethylamine (294 mg,
2.91 mmol) and methanesulfonyl chloride (280 mg, 2.44 mmol) at -20 °C
under a nitrogen atmosphere. After stirring the solution at the same
temperature for 3 hours, the reaction was quenched by addition of 3%
hydrochloric acid (10 mL), and the mixture was then warmed to room
temperature. The resulting solution was extracted with ethyl acetate (100
mL). The combined organic extracts were washed with 3% hydrochloric
acid (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to provide a crude material (461 mg) which was
used in the next step without further purification. Rf = 0.26 (silica gel,
hexane/EtOAc = 2/1).
To a suspension of sodium hydride (60% oil suspension, 84.3 mg, 2.11
mmol) in tetrahydrofuran (3.8 mL) was added thiophenol (320 mg, 2.90
mmol) at 0 °C under a nitrogen atmosphere. After stirring the solution at
the same temperature for 10 minutes, the resulting solution was added to
a solution of the crude material (461 mg) in tetrahydrofuran (6.4 mL) at
0 °C and stirred for 30 minutes at the same temperature. The reaction
was quenched by addition of water (20 mL), and the mixture was then
warmed to room temperature. The solvent was removed under reduced
pressure, and the resulting residue was extracted with ethyl acetate (30
mL). The combined organic extracts were washed with saturated
aqueous sodium sulfite (10 mL×2) and brine (10 mL×2), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a crude material.
This material was purified by column chromatography (silica gel,
hexane/EtOAc = 7/1 to 4/1) and recrystallization (hexane/EtOAc) to give
4f (262 mg, 1.03 mmol, 57%) as a yellow solid. Rf = 0.28 (silica gel,
hexane/EtOAc = 3/1); m.p. 54–56 °C; IR (KBr) 2891 (C–H), 1705 (C=O)
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.39-7.35 (m, 3H, ArH), 7.26-7.15 (m,
4H, ArH), 7.07 (dt, J = 0.9, 7.5 Hz, 1H, ArH), 6.64 (d, J = 7.5 Hz, 1H,
ArH), 4.57 (s, 1H, CH), 3.03 (s, 1H, CH3); 13C NMR (75 MHz, CDCl3) δ
174.2 (C), 143.8 (C), 136.7 (CH), 134.1 (CH), 130.9 (C), 128.9 (CH),
128.5 (CH), 126.1 (C), 125.2 (CH), 122.7 (CH), 108.0 (CH), 49.1 (CH),
Synthesis and characterization of 5b: To a solution of I (596 mg, 3.36
mmol) in dichloromethane (17 mL) were added di-tert-butyl dicarbonate
(733 mg, 3.36 mmol) and N,N-dimethyl-4-aminopyridine (15.0 mg, 0.122
mmol) under a nitrogen atmosphere at room temperature. The mixture
was stirred at the same temperature for 1 hour and concentrated in
vacuo to provide a crude material. This material was purified by column
chromatography (silica gel, hexane/EtOAc = 4/1) and recrystallization
(hexane/EtOAc) to give 5b (787 mg, 2.84 mmol, 85%) as a white solid. Rf
= 0.53 (silica gel, hexane/EtOAc = 2/1); m.p. 93–95 °C; IR (KBr) 3340
(N–H), 2984 (C–H), 1742 (C=O), 1667 (C=O), 1631 (C=C) cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.14 (brs, 1H, NH), 7.59 (d, J = 7.8 Hz, 2H, ArH),
7.35 (t, J = 7.8 Hz, 2H, ArH), 7.13 (t, J = 7.8 Hz, 1H, ArH), 6.20 (s, 1H,
CH2), 5.80 (s, 1H, CH2), 4.91 (d, J = 0.9 Hz, 2H, CH2), 1.51 (s, 9H, CH3);
13C NMR (75 MHz, CDCl3) δ 163.9 (C), 153.4 (C), 139.4 (C), 137.7 (C),
129.0 (CH), 125.0 (CH), 124.5 (CH2), 120.1 (CH), 83.2 (C), 65.7 (CH2),
27.7 (CH3). Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found:
C, 64.85; H, 6.75; N, 4.95.
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10.1002/ejoc.201800084
European Journal of Organic Chemistry
FULL PAPER
Synthesis and characterization of 5c: To a solution of I (355 mg, 2.00
mmol) in dichloromethane (10 mL) were added benzoyl chloride (350 mg,
2.49 mmol) and triethylamine (309 mg, 3.05 mmol) under a nitrogen
atmosphere at room temperature. The mixture was stirred at the same
temperature for 13 hours. The reaction was quenched by addition of
water (10 mL), and the resulting mixture was extracted with ethyl acetate
(30 mL). The combined organic extracts were washed with 1.0 M
aqueous sodium hydroxide (10 mL) and brine (20 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to provide a crude material.
This material was purified by column chromatography (silica gel,
hexane/EtOAc = 3/1) and recrystallization (hexane/EtOAc) to give 5c
(276 mg, 0.960 mmol, 48%) as a white solid. Rf = 0.51 (silica gel,
hexane/EtOAc = 2/1); m.p. 84–86 °C; IR (KBr) 3317 (N–H), 1721 (C=O),
1663 (C=O), 1629 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 8.19 (brs,
1H, NH), 8.10-8.07 (m, 2H, ArH), 7.63-7.57 (m, 3H, ArH), 7.46 (t, J = 7.2
Hz, 2H, ArH), 7.35 (t, J = 7.2 Hz, 2H, ArH), 7.14 (t, J = 7.2 Hz, 1H, ArH),
6.22 (s, 1H, CH2), 5.87 (s, 1H, CH2), 5.20 (d, J = 0.6 Hz, 2H, CH2); 13C
NMR (75 MHz, CDCl3) δ 166.5 (C), 164.1 (C), 139.8 (C), 137.6 (C), 133.4
(CH), 129.7 (CH), 129.4 (C), 129.0 (CH), 128.5 (CH), 124.6 (CH), 124.5
(CH2), 120.1 (CH), 63.7 (CH2). Anal. Calcd for C17H15NO3: C, 72.58; H,
5.37; N, 4.98. Found: C, 72.36; H, 5.57; N, 5.06.
Synthesis and characterization of 5g: According to the synthetic
procedure of 5a, 5g was prepared from N-ethylmethacrylamide (1.72 g,
15.2 mmol). The crude product was purified by column chromatography
(silica gel, hexane/EtOAc = 1/1) to give 5g (0.646 g, 3.77 mmol, 25%) as
a colorless oil. Rf = 0.23 (silica gel, hexane/EtOAc = 1/1); IR (KBr) 3290
(N–H), 1739 (C=O), 1664 (C=O), 1620 (C=C) cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.08 (brs, 1H, NH), 5.95 (s, 1H, CH2), 5.61 (s, 1H, CH2), 4.84 (d,
J = 0.9 Hz, 2H, CH2), 3.37 (dq, J = 5.7, 7.2 Hz, 2H, CH2), 2.11 (s, 3H,
CH3), 1.19 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 170.5
(C), 165.9 (C), 139.3 (C), 121.9 (CH2), 63.3 (CH2), 34.4 (CH2), 20.8 (CH3),
14.5 (CH3). Anal. Calcd for C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found:
C, 55.88; H, 7.57; N, 7.90.
General procedure for the synthesis of 2a-i: All the experiments for
the synthesis of 2a-i were carried out as described in the following typical
procedure. The reaction of 4a with 5a for the synthesis of 2a was
exemplified as follows.
Synthesis and characterization of 2a: To a stirred solution of 4a (52.5
mg, 0.200 mmol) and 5a (51.8 mg, 0.236 mmol) in dichloromethane (0.20
M) was added Pd(PPh3)4 (10 mol%). The resulting yellow solution was
stirred for 30 min at room temperature and concentrated under reduced
pressure to give a crude material. This material was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2a (83.7 mg, 0.199 mmol, >99%) as a white solid. Rf = 0.23 (silica
gel, hexane/EtOAc = 1/1); m.p. 238–240 °C; IR (KBr) 3345 (N–H), 3288
(N–H), 2981 (C–H), 2925 (C–H), 1713 (C=O), 1686 (C=O), 1626 (C=C)
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.58 (brs, 1H, NH), 7.49 (d, J = 7.5 Hz,
2H, ArH), 7.33 (t, J = 7.5 Hz, 2H, ArH), 7.28-7.20 (m, 2H, ArH), 7.14 (t, J
= 7.5 Hz, 1H, ArH), 6.98 (t, J = 7.5 Hz, 1H, ArH), 6.82 (d, J = 7.5 Hz, 1H,
ArH), 6.54 (brs, 1H, NH), 5.76 (s, 1H, CH2), 5.24 (s, 1H, CH2), 3.23 (s, 3H,
CH3), 2.89 (d, J = 13.5 Hz, 1H, CH2), 2.75 (d, J = 13.5 Hz, 1H, CH2), 1.21
(s, 9H, CH3); 13C NMR (75 MHz, DMSO-d6, 50 °C) δ 175.5 (C), 166.4 (C),
153.2 (C), 143.2 (C), 138.5 (C), 138.1 (C), 129.6 (C), 128.0 (CH), 123.4
(CH2), 123.3 (CH), 122.6 (CH), 121.3 (CH), 120.4 (CH), 107.7 (CH), 78.3
(C), 61.3 (C), 38.2 (CH2), 27.6 (CH3), 25.7 (CH3). Anal. Calcd for
C24H27N3O4: C, 68.39; H, 6.46; N, 9.97. Found: C, 68.23; H, 6.45; N, 9.73.
Synthesis and characterization of 5d: According to the synthetic
procedure of 5a, 5d was prepared from N-(p-anis)methacrylamide (1.43
g, 7.48 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 3/1) to give 5d (0.445 g,
1.79 mmol, 24%) as a white solid. Rf = 0.20 (silica gel, hexane/EtOAc =
2/1); m.p. 95–97 °C; IR (KBr) 3292 (N–H), 2960 (C–H), 1743 (C=O),
1661 (C=O), 1624 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 8.01 (brs,
1H, NH), 7.49 (d, J = 9.0 Hz, 2H, ArH), 6.88 (d, J = 9.0 Hz, 2H, ArH),
6.13 (s, 1H, CH2), 5.74 (s, 1H, CH2), 4.92 (s, 2H, CH2), 3.80 (s, 3H, CH3),
2.13 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 171.0 (C), 163.8 (C),
156.6 (C), 139.7 (C), 130.7 (C), 124.3 (CH2), 121.8 (CH), 114.2 (CH),
63.4 (C H2), 55.5 (CH3), 20.9 (CH3). Anal. Calcd for C13H15NO4: C, 62.64;
H, 6.07; N, 5.62. Found: C, 62.69; H, 6.18; N, 5.72.
Synthesis and characterization of 5e: According to the synthetic
procedure
of
5a,
5e
was
prepared
from
N-(p-tert-
butylphenyl)methacrylamide (687 mg, 3.16 mmol). The crude product
was purified by column chromatography (silica gel, hexane/EtOAc = 3/1)
to give 5e (512 mg, 1.86 mmol, 59%) as a white solid. Rf = 0.37 (silica
gel, hexane/EtOAc = 2/1); m.p. 90–92 °C; IR (KBr) 3384 (N–H), 2962 (C–
H), 1730 (C=O), 1671 (C=O), 1631 (C=C) cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.03 (brs, 1H, NH), 7.50 (d, J = 8.7 Hz, 2H, ArH), 7.36 (d, J =
8.7 Hz, 2H, ArH), 6.12 (s, 1H, CH2), 5.74 (s, 1H, CH2), 4.92 (s, 2H, CH2),
2.12 (s, 3H, CH3), 1.31 (s, 9H, CH3); 13C NMR (75 MHz, CDCl3) δ 170.9
(C), 164.0 (C), 147.6 (C), 139.9 (C), 135.0 (C), 125.8 (CH), 124.2 (CH2),
119.8 (CH), 63.4 (CH2), 34.4 (C), 31.3 (CH3), 20.9 (CH3). Anal. Calcd for
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.86; H, 7.53; N, 5.33.
Synthesis and characterization of 2b: According to the synthetic
procedure of 2a, 2b was synthesized from 4a (52.4 mg, 0.200 mmol) and
5d (59.1 mg, 0.237 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2b (89.8 mg, 0.199 mmol, >99%) as a white solid. Rf = 0.29 (silica
gel, hexane/EtOAc = 1/2); m.p. 178–180 °C; IR (KBr) 3347 (N–H), 3294
(N–H), 2979 (C–H), 2931 (C–H), 1715 (C=O), 1686 (C=O), 1617 (C=C)
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.54 (brs, 1H, NH), 7.39 (d, J = 9.0 Hz,
2H, ArH), 7.28-7.19 (m, 2H, ArH), 6.99 (t, J = 7.5 Hz, 1H, ArH), 6.89-6.81
(m, 3H, ArH), 6.68 (brs, 1H, NH), 5.75 (s, 1H, CH2), 5.21 (s, 1H, CH2),
3.80 (s, 3H, CH3), 3.23 (s, 3H, CH3), 2.89 (d, J = 13.5 Hz, 1H, CH2), 2.71
(d, J = 13.5 Hz, 1H, CH2), 1.22 (brs, 9H, CH3); 13C NMR (75 MHz, CDCl3)
δ 176.6 (C), 167.5 (C), 156.5 (C), 153.9 (C), 142.8 (C), 138.8 (C), 130.6
(C), 130.1 (C), 128.7 (CH), 123.8 (CH2), 123.4 (CH), 122.3 (CH), 122.2
(CH), 121.9 (CH), 113.9 (CH), 108.0 (CH), 79.8 (C), 61.5 (C), 55.4 (CH3),
39.7 (CH2), 28.0 (CH3), 26.4 (CH3). Anal. Calcd for C25H29N3O5: C, 66.50;
H, 6.47; N, 9.31. Found: C, 66.40; H, 6.55; N, 9.07.
Synthesis and characterization of 5f: According to the synthetic
procedure of 5a, 5f was prepared from N-(1-naphthyl)methacrylamide
(635 mg, 3.01 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 3/1) to give 5f (327 mg, 1.21
mmol, 40%) as a white solid. Rf = 0.25 (silica gel, hexane/EtOAc = 2/1);
m.p. 63–65 °C; IR (KBr) 3299 (N–H), 3055 (C–H), 1736 (C=O), 1660
(C=O), 1626 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 8.37 (brs, 1H, NH),
8.01 (d, J = 7.2 Hz, 1H, ArH), 7.88 (m, 2H, ArH), 7.73 (d, J = 8.4 Hz, 1H,
ArH), 7.57-7.47 (m, 3H, ArH), 6.26 (s, 1H, CH2), 5.83 (s, 1H, CH2), 5.01
(s, 2H, CH2), 2.18 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 170.5 (C),
164.7 (C), 139.6 (C), 134.1 (C), 132.0 (C), 128.9 (CH), 127.0 (C), 126.4
(CH), 126.0 (CH), 125.7 (CH), 124.7 (CH2), 120.8 (CH), 120.4 (CH), 63.7
(C H2), 21.0 (CH3). Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20.
Found: C, 71.51; H, 5.64; N, 5.26.
Synthesis and characterization of 2c: According to the synthetic
procedure of 2a, 2c was synthesized from 4a (52.3 mg, 0.199 mmol) and
5e (64.6 mg, 0.235 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2c (94.2 mg, 0.197 mmol, 99%) as a white solid. Rf = 0.28 (silica
gel, hexane/EtOAc = 1/1); m.p. 215–217 °C; IR (KBr) 3330 (N–H), 3276
(N–H), 2967 (C–H), 1715 (C=O), 1685 (C=O), 1618 (C=C) cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.78 (brs, 1H, NH), 7.42 (d, J = 8.4 Hz, 2H, ArH),
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10.1002/ejoc.201800084
European Journal of Organic Chemistry
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7.34 (d, J = 8.4 Hz, 2H, ArH), 7.26 (dt, J = 1.5, 8.1 Hz, 1H, ArH), 7.18 (d,
J = 7.5 Hz, 1H, ArH), 6.98 (t, J = 7.5 Hz, 1H, ArH), 6.86 (brs, 1H, NH),
6.81 (d, J = 7.5 Hz, 1H, ArH), 5.76 (s, 1H, CH2), 5.19 (s, 1H, CH2), 3.21
(s, 3H, CH3), 2.88 (d, J = 13.5 Hz, 1H, CH2), 2.66 (d, J = 13.5 Hz, 1H,
CH2), 1.31 (s, 9H, CH3), 1.21 (brs, 9H, CH3); 13C NMR (75 MHz, CDCl3) δ
176.5 (C), 167.6 (C), 153.9 (C), 147.6 (C), 142.9 (C), 139.3 (C), 134.8
(C), 130.1 (C), 128.8 (CH), 125.7 (CH), 123.5 (CH2), 123.3 (CH), 122.3
(CH), 120.2 (CH), 108.0 (CH), 79.9 (C), 61.5(C), 39.7 (CH2), 34.4 (C),
31.3 (CH3), 28.0 (CH3), 26.4 (CH3). Anal. Calcd for C28H35N3O4: C, 70.42;
H, 7.39; N, 8.80. Found: C, 70.32; H, 7.07; N, 8.77.
(CH2), 27.8 (CH3). Anal. Calcd for C29H29N3O4: C, 72.03; H, 6.05; N, 8.69.
Found: C, 71.84; H, 6.10; N, 8.44.
Synthesis and characterization of 2g: According to the synthetic
procedure of 2a, 2g was synthesized from 4c (49.5 mg, 0.200 mmol) and
5a (51.1 mg, 0.233 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2g (76.1 mg, 0.187 mmol, 94%) as a white solid. Rf = 0.13 (silica
gel, hexane/EtOAc = 1/1); m.p. 160–162 °C; IR (KBr) 3332 (N–H), 2979
(C–H), 2928 (C–H), 1732 (C=O), 1699 (C=O), 1666 (C=O), 1621 (C=C)
cm-1; 1H NMR (300 MHz, CD3OD) δ 7.36 (d, J = 8.1 Hz, 2H, ArH), 7.25 (t,
J = 7.5 Hz, 2H, ArH), 7.14-7.04 (m, 3H, ArH), 6.90-6.82 (m, 2H, ArH),
5.80 (s, 1H, CH2), 5.36 (s, 1H, CH2), 3.17 (d, J = 13.2 Hz, 1H, CH2), 2.63
(d, J = 13.2 Hz, 1H, CH2), 1.28 (s, 9H, CH3); 13C NMR (75 MHz, DMSO-
d6, 50 °C) δ 177.3 (C), 166.7 (C), 153.4 (C), 141.7 (C), 138.5 (C), 138.0
(C), 130.4 (C), 128.0 (CH), 127.8 (CH), 123.8 (CH2), 123.3 (CH), 123.1
(CH), 120.6 (CH), 120.4 (CH), 109.1 (CH), 78.4 (C), 61.4 (C), 38.1 (CH2),
27.6 (CH3). Anal. Calcd for C23H25N3O4: C, 67.80; H, 6.18; N, 10.31.
Found: C, 67.52; H, 6.19; N, 10.58.
Synthesis and characterization of 2d: According to the synthetic
procedure of 2a, 2d was synthesized from 4a (52.6 mg, 0.201 mmol) and
5f (64.8 mg, 0.241 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2d (91.3 mg, 0.194 mmol, 97%) as a white solid. Rf = 0.21 (silica
gel, hexane/EtOAc = 1/1); m.p. 210–212 °C; IR (KBr) 3329 (N–H), 2977
(C–H), 2926 (C–H), 1712 (C=O), 1656 (C=O), 1617 (C=C) cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.00 (brs, 1H, NH), 7.89-7.81 (m, 3H, ArH), 7.73 (d,
J = 8.1 Hz, 1H, ArH), 7.54-7.46 (m, 3H, ArH), 7.28-7.21 (m, 2H, ArH),
7.00 (t, J = 7.5 Hz, 1H, ArH), 6.83 (d, J = 7.5 Hz, 1H, ArH), 6.53 (brs, 1H,
NH), 5.92 (s, 1H, CH2), 5.34 (s, 1H, CH2), 3.26 (s, 3H, CH3), 2.91 (d, J =
Synthesis and characterization of 2h: According to the synthetic
procedure of 2a, 2h was synthesized from 4d (32.6 mg, 0.200 mmol) and
5a (51.3 mg, 0.234 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2h (51.3 mg, 0.159 mmol, 80%) as a white solid. Rf = 0.28 (silica
gel, hexane/EtOAc = 1/2); m.p. 184–186 °C; IR (KBr) 3380 (N–H), 3304
(O–H), 1719 (C=O), 1655 (C=O), 1618 (C=C) cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.00 (brs, 1H, NH), 7.52 (d, J = 8.1 Hz, 2H, ArH), 7.36-7.28 (m,
4H, ArH), 7.14 (t, J = 7.5 Hz, 1H, ArH), 7.04 (t, J = 7.5 Hz, 1H, ArH), 6.82
(d, J = 7.5 Hz, 1H, ArH), 5.91 (s, 1H, CH2), 5.37 (s, 1H, CH2), 5.32 (s, 1H,
OH), 3.17 (s, 3H, CH3), 3.08 (d, J = 14.1 Hz, 1H, CH2), 2.77 (d, J = 14.1
Hz, 1H, CH2); 13C NMR (75 MHz, DMSO-d6) δ 176.8 (C), 166.5 (C),
143.1 (C), 139.3 (C), 138.9 (C), 130.0 (C), 129.0 (CH), 128.3 (CH), 124.4
(CH), 123.3 (CH), 122.6 (CH2), 121.8 (CH), 120.3 (CH), 108.3 (CH), 75.4
(C), 25.8 (CH3). Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69.
Found: C, 70.75; H, 5.88; N, 8.54.
13.5 Hz, 1H, CH2), 2.84 (d, J = 13.5 Hz, 1H, CH2), 1.18 (s, 9H, CH3); 13
C
NMR (75 MHz, CDCl3) δ 176.3 (C), 168.5 (C), 153.8 (C), 142.9 (C), 139.7
(C), 134.0 (C), 131.9 (C), 130.2 (C), 128.8 (CH), 128.6 (CH), 127.5 (C),
126.4 (CH), 126.3 (CH), 126.0 (CH), 125.6 (CH), 123.3 (CH), 123.2 (CH2),
122.4 (CH), 121.5 (CH), 121.0 (CH), 108.0 (CH), 79.9 (C), 61.6 (C), 39.8
(CH2), 28.0 (CH3), 26.4 (CH3). Anal. Calcd for C28H29N3O4: C, 71.32; H,
6.20; N, 8.91. Found: C, 71.15; H, 6.13; N, 8.67.
Synthesis and characterization of 2e: According to the synthetic
procedure of 2a, 2e was synthesized from 4a (52.5 mg, 0.200 mmol) and
5g (40.0 mg, 0.234 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2e (73.3 mg, 0.196 mmol, 98%) as a white solid. Rf = 0.28 (silica
gel, hexane/EtOAc = 1/2); m.p. 178–180 °C; IR (KBr) 3367 (N–H), 3290
(N–H), 2983 (C–H), 2929 (C–H), 1709 (C=O), 1690 (C=O), 1657 (C=O),
1617 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H, ArH),
7.15 (d, J = 6.9 Hz, 1H, ArH), 7.00 (t, J = 7.5 Hz, 1H, ArH), 6.81 (d, J =
7.5 Hz, 1H, ArH), 5.92 (brs, 1H, NH), 5.61 (s, 1H, CH2), 5.08 (s, 1H, CH2),
3.37-3.25 (m, 2H, CH2), 3.23 (s, 3H, CH3), 2.82 (d, J = 13.5 Hz, 1H, CH2),
2.55 (d, J = 13.5 Hz, 1H, CH2), 1.26 (brs, 9H, CH3), 1.16 (t, J = 7.5 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3) δ 176.5 (C), 169.5 (C), 153.9 (C),
142.9 (C), 139.0 (C), 130.2 (C), 128.6 (CH), 123.4 (CH), 122.7 (CH2),
122.1 (CH), 107.9 (CH), 79.6 (C), 61.4 (C), 39.8 (CH2), 34.9 (CH2), 28.1
(CH3), 26.4 (CH3), 14.6 (CH3). Anal. Calcd for C20H27N3O4: C, 64.32; H,
7.29; N, 11.25. Found: C, 64.03; H, 7.26; N, 10.90.
Synthesis and characterization of 2i: According to the synthetic
procedure of 2a, 2i was synthesized from 4e (53.9 mg, 0.205 mmol) and
5a (53.0 mg, 0.242 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2i (36.2 mg, 0.0857 mmol, 42%) as a white solid. Rf = 0.18 (silica
gel, hexane/EtOAc = 2/1); m.p. 126–128 °C; IR (NaCl) 3583 (N–H), 3496
(O–H), 3012 (C–H), 2982 (C–H), 2934 (C–H), 1750 (C=O), 1725 (C=O),
1669 (C=O), 1618 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.92 (brs,
1H, NH), 7.51 (d, J = 7.5 Hz, 2H, ArH), 7.33-7.24 (m, 4H, ArH), 7.10 (t, J
= 7.5 Hz, 1H, ArH), 7.01 (t, J = 7.5 Hz, 1H, ArH), 6.85 (d, J = 7.5 Hz, 1H,
ArH), 5.88 (s, 1H, CH2), 5.24 (s, 1H, CH2), 3.24 (s, 3H, CH3), 3.13 (d, J =
Synthesis and characterization of 2f: According to the synthetic
procedure of 2a, 2f was synthesized from 4b (64.9 mg, 0.200 mmol) and
5a (51.4 mg, 0.234 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to CHCl3/MeOH = 50/1)
to give 2f (96.2 mg, 0.199 mmol, >99%) as a white solid. Rf = 0.25 (silica
gel, hexane/EtOAc = 1/1); m.p. 204–206 °C; IR (KBr) 3342 (N–H), 2978
(C–H), 2924 (C–H), 1716 (C=O), 1697 (C=O), 1657 (C=O), 1611 (C=C)
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.60 (brs, 1H, NH), 7.54-7.28 (m, 10H,
ArH), 7.20-7.11 (m, 2H, ArH), 7.02 (t, J = 7.5 Hz, 1H, ArH), 6.82 (brd, J =
7.4 Hz, 1H, ArH), 6.54 (brs, 1H, NH), 5.79 (s, 1H, CH2), 5.34 (s, 1H, CH2),
2.99 (d, J = 13.8 Hz, 1H, CH2), 2.93 (d, J = 13.8 Hz, 1H, CH2), 1.25 (s,
9H, CH3); 13C NMR (75 MHz, DMSO-d6, 50 °C) δ 175.0 (C), 166.2 (C),
153.5 (C), 142.8 (C), 138.4 (C), 138.0 (C), 134.5 (C), 129.5 (C), 129.0
(CH), 128.0 (CH), 127.4 (CH), 126.3 (CH), 123.6 (CH2), 123.3 (CH),
123.2 (CH), 122.0 (CH), 120.6 (CH), 108.3 (CH), 78.6 (C), 61.3 (C), 38.3
14.1 Hz, 1H, CH2), 3.02 (d, J = 14.1 Hz, 1H, CH2), 1.30 (s, 9H, CH3); 13
C
NMR (75 MHz, CDCl3) δ 174.1 (C), 166.4 (C), 150.3 (C), 143.4 (C), 138.3
(C), 137.9 (C), 130.2 (CH), 128.7 (CH), 126.4 (C), 124.9 (CH2), 124.2
(CH), 123.7 (CH), 122.9 (CH), 120.1 (CH), 108.4 (CH), 83.7 (C), 80.3 (C),
39.0 (CH2), 27.4 (CH3), 26.5 (CH3). Anal. Calcd for C24H26N2O5: C, 68.23;
H, 6.20; N, 6.63. Found: C, 67.93; H, 6.40; N, 6.84.
Synthesis and characterization of 2j: According to the synthetic
procedure of 2a, 2j was synthesized from 4f (50.8 mg, 0.199 mmol) and
5a (52.1 mg, 0.238 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 3/1 to 2/1) to give 2j (75.5
mg, 0.182 mmol, 91%) as
a white solid. Rf = 0.18 (silica gel,
hexane/EtOAc = 2/1); m.p. 46–48 °C; IR (NaCl) 3312 (N-H), 3006 (C-H),
1713 (C=O), 1669 (C=O), 1612 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ
7.67 (brs, 1H, NH), 7.39-7.36 (m, 3H, ArH), 7.30-7.22 (m, 3H, ArH), 7.20-
7.05 (m, 6H, ArH), 7.00 (dt, J = 0.9, 7.5 Hz, 1H, ArH), 6.49 (d, J = 7.5 Hz,
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10.1002/ejoc.201800084
European Journal of Organic Chemistry
FULL PAPER
1H, ArH), 5.69 (s, 1H, CH2), 5.26 (s, 1H, CH2), 3.42 (dd, J = 0.9, 14.1 Hz,
1H, CH2), 3.21 (d, J = 14.1 Hz, 1H, CH2), 2.87 (s, 3H, CH3); 13C NMR (75
MHz, CDCl3) δ 176.0 (C), 166.3 (C), 143.0 (C), 140.4 (C), 137.7 (C),
136.7 (CH), 129.7 (CH), 129.0 (CH), 128.9 (C), 128.7 (CH), 128.2 (C,
CH), 125.3 (CH), 124.2 (CH), 123.7 (CH2), 122.9 (CH), 120.2 (CH), 107.8
(CH), 59.0 (C), 35.6 (CH2), 26.1 (CH3). Anal. Calcd for C25H22N2O2S: C,
72.44; H, 5.35; N, 6.76. Found: C, 72.32; H, 5.39; N, 6.51.
To a solution of 6a (136 mg, 0.414 mmol) in dichloromethane (4.1 mL)
was added trifluoroacetic acid (12.7 mg, 0.111 mmol) under a nitrogen
atmosphere at room temperature. After stirring the solution at the same
temperature for 24 hours, the resulting mixture was concentrated under
reduced pressure. The crude residue was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1 to 1/2) to give 3a (93.4
mg, 0.409 mmol, 99%) as
a white solid. Rf = 0.15 (silica gel,
hexane/EtOAc = 1/2); m.p. 174–176 °C; IR (KBr) 3176 (N-H), 3059 (C-H),
1735 (C=O), 1721 (C=O), 1660 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ
7.37 (dt, J = 1.2, 7.5 Hz, 1H, ArH), 7.30 (t, J = 7.5 Hz, 1H, ArH), 7.12 (dt,
J = 1.2, 7.5 Hz, 1H, ArH), 6.88 (d, J = 7.5 Hz, 1H, ArH), 6.18 (t, J = 2.7
Hz, 1H, CH2), 5.92 (brs, 1H, NH), 5.51 (t, J = 2.7 Hz, 1H, CH2), 3.22 (td, J
= 2.6, 17.0 Hz, 1H, CH2), 3.23 (s, 3H, CH3), 2.94 (td, J = 2.6, 17.0 Hz, 1H,
CH2); 13C NMR (75 MHz, CDCl3) 176.2 (C), 170.4 (C), 143.0 (C), 136.7
(C), 130.2 (CH), 129.6 (C), 123.6 (CH), 123.5 (CH), 117.5 (CH2), 108.7
(CH), 60.8 (C), 38.4 (CH2), 26.6 (CH3). Anal. Calcd for C13H12N2O2: C,
68.41; H, 5.30; N, 12.27. Found: C, 68.63; H, 5.45; N, 12.13.
Synthesis and characterization of 2k: According to the synthetic
procedure of 2a, 2k was synthesized from 4g (29.9 mg, 0.200 mmol) and
5a (51.4 mg, 0.234 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 1/4) to give 2k (51.2 mg) as
a mixture with a bisallylated derivative (68% NMR yield). Rf = 0.32 (silica
gel, hexane/EtOAc = 1/3); m.p. 91–93 °C; IR (KBr) 3252 (N-H), 3061 (C-
H), 2962 (C-H), 1732 (C=O), 1642 (C=O), 1621 (C=C) cm-1; 1H NMR
(300 MHz, CD3OD) δ 7.35-7.21 (m, 5H, ArH), 7.13 (dt, J = 1.2, 7.5 Hz,
1H, ArH), 7.06 (tt, J = 1.2, 7.5 Hz, 1H, ArH), 6.88 (dt, J = 0.9, 7.5 Hz, 1H,
ArH), 6.83 (d, J = 7.8 Hz, 1H, ArH), 5.77 (s, 1H, CH2), 5.39 (s, 1H, CH2),
3.25 (d, J = 13.2 Hz, 1H, CH2), 2.84 (d, J = 13.2 Hz, 1H, CH2); 13C NMR
(75 MHz, CD3OD) δ 181.3 (C), 169.5 (C), 142.6 (C), 140.9 (C), 139.4 (C),
131.4 (C), 130.7 (CH), 129.5 (CH), 126.4 (CH), 125.4 (CH), 124.1 (CH2),
123.4 (CH), 122.3 (CH), 111.2 (CH), 77.7 (C), 40.7 (CH2). Anal. Calcd for
C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 69.76; H, 5.17; N, 8.92.
According to the above synthetic procedure, 6a was obtained from 2b
(77.2 mg, 0.171 mmol) in 99% yield (55.8 mg, 0.170 mmol).
According to the above synthetic procedure, 6a was obtained from 2c
(64.8 mg, 0.136 mmol) in 95% yield (42.5 mg, 0.129 mmol).
Synthesis and characterization of 2l: According to the synthetic
procedure of 2a, 2l was synthesized from 4h (48.2 mg, 0.200 mmol) and
5a (51.9 mg, 0.237 mmol). The crude product was purified by column
chromatography (silica gel, hexane/EtOAc = 2/1) to give 2l (65.9 mg,
0.165 mmol, 83%) as a white solid. Rf = 0.25 (silica gel, hexane/EtOAc =
1/1); m.p. 66–68 °C; IR (KBr) 3253 (N-H), 3058 (C-H), 2962 (C-H), 1719
(C=O), 1707 C=O), 1656 (C=O), 1620 (C=C) cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.62 (brs, 1H, NH), 7.57 (brs, 1H, NH), 7.32-6.91 (m, 13H, ArH),
6.56 (d, J = 7.8 Hz, 1H, ArH), 5.59 (s, 1H, CH2), 5.28 (s, 1H, CH2), 3.44
(d, J = 13.8 Hz, 1H, CH2), 3.12 (d, J = 13.8 Hz, 1H, CH2); 13C NMR (75
MHz, CD3OD) δ 179.5 (C), 169.3 (C), 142.7 (C), 141.9 (C), 139.2 (C),
137.6 (CH), 130.6 (CH), 130.1 (CH), 129.7 (C), 129.5 (CH), 129.4 (CH),
127.2 (CH), 125.4 (CH), 123.3 (CH), 123.2 (CH2), 122.4 (CH), 110.8 (CH),
61.0 (C), 37.5 (CH2). Anal. Calcd for C24H20N2O2S: C, 71.98; H, 5.03; N,
6.99. Found: C, 71.83; H, 5.33; N, 7.28.
According to the above synthetic procedure, 6a was obtained from 2d
(39.5 mg, 0.0838 mmol) in 99% yield (27.2 mg, 0.0828 mmol).
According to the above synthetic procedure, 6a was obtained from 2e
(70.7 mg, 0.189 mmol) in 98% yield (60.8 mg, 0.185 mmol).
Synthesis and characterization of 3b: According to the above synthetic
procedure, 6b was obtained from 2f (287 mg, 0.594 mmol) in 96% yield
(225 mg, 0.576 mmol) as
a white solid. Rf = 0.38 (silica gel,
hexane/EtOAc = 2/1); m.p. 50–52 °C; IR (KBr) 3019 (C-H), 2983 (C-H),
1785 (C=O), 1742 (C=O), 1718 (C=O), 1609 (C=C) cm-1; 1H NMR (300
MHz, CDCl3) δ 7.57-7.42 (m, 5H, ArH), 7.31-7.24 (m, 2H, ArH), 7.12 (dt,
J = 0.9, 7.5 Hz, 1H, ArH), 6.95 (d, J = 7.8 Hz, 1H, ArH), 6.39 (t, J = 2.7
Hz, 1H, CH2), 5.61 (t, J = 2.7 Hz, 1H, CH2), 3.24 (td, J = 2.7, 16.8 Hz, 1H,
CH2), 2.92 (td, J = 2.7, 16.8 Hz, 1H, CH2), 1.29 (s, 9H, CH3); 13C NMR
(75 MHz, CDCl3) 174.6 (C), 166.0 (C), 148.8 (C), 142.9 (C), 135.9 (C),
134.1 (C), 130.0 (C), 129.6 (CH), 129.5 (CH), 128.1 (CH), 125.9 (CH),
123.7 (CH), 122.0 (CH), 121.1 (CH2), 109.9 (CH), 84.2 (C), 64.1 (C), 36.8
(CH2), 27.7 (CH3). Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.18.
Found: C, 70.79; H, 5.63; N, 7.48.
General procedure for the synthesis of 3a-c: All the experiments for
the synthesis of 2a-i were carried out as described in the following typical
procedure. The transformation of 2a to 3a was exemplified as follows.
Synthesis and characterization of 3a: To a solution of 2a (143 mg,
0.339 mmol) in dichloromethane (0.34 mL) was added Boc2O (220 mg,
1.01 mmol), triethylamine (102 mg, 1.01 mmol) and N,N-dimethyl-4-
aminopyridine (12.2 mg, 0.100 mmol) at room temperature under a
nitrogen atmosphere. After stirring the solution at the same temperature
for 24 hours, the solvent was removed under reduced pressure. The
crude residue was purified by column chromatography (silica gel,
hexane/EtOAc = 3/1 to 2/1) to give N-Boc protected spirocyclic lactam 6a
(108 mg, 0.329 mmol, 97%) as a white solid. Rf = 0.30 (silica gel,
hexane/EtOAc = 1/1); m.p. 149–151 °C; IR (NaCl) 3018 (C-H), 1782
(C=O), 1734 (C=O), 1615 (C=C) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36
(dt, J = 1.0, 7.5 Hz, 1H, ArH), 7.17 (dd, J = 1.0, 7.5 Hz, 1H, ArH), 7.06
(dd, J = 1.0, 7.5 Hz, 1H, ArH), 6.87 (d, J = 7.5 Hz, 1H, ArH), 6.38 (t, J =
2.6 Hz, 1H, CH2), 5.59 (t, J = 2.6 Hz, 1H, CH2), 3.25 (s, 3H, CH3), 3.12
(td, J = 2.6, 16.8 Hz, 1H, CH2), 2.78 (td, J = 2.6, 16.8 Hz, 1H, CH2), 1.19
(s, 9H, CH3); 13C NMR (75 MHz, CDCl3) 175.2 (C), 166.3 (C), 148.3 (C),
142.9 (C), 135.8 (C), 130.1 (C), 129.7 (CH), 123.2 (CH), 121.6 (CH),
120.9 (CH2), 108.5 (CH), 83.7 (C), 63.9 (C), 36.3 (CH2), 27.4 (CH3), 26.5
(CH3). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C,
65.45; H, 6.38; N, 8.60.
In this procedure, 3b was obtained from 6b (135 mg, 0.346 mmol) in 99%
yield (99.5 mg, 0.343 mmol) as a white solid. Rf = 0.45 (silica gel,
hexane/EtOAc = 1/2); m.p. 252–254 °C; IR (KBr) 3477 (N-H), 3177 (N-H),
3063 (C-H), 1735 (C=O), 1700 (C=O), 1658 (C=C) cm-1; 1H NMR (300
MHz, DMSO-d6) δ 8.71 (brs, 1H, NH), 7.59 (t, J = 7.2 Hz, 2H, ArH), 7.48-
7.42 (m, 4H, ArH), 7.31 (t, J = 7.8 Hz, 1H, ArH), 7.16 (t, J = 7.5 Hz, 1H,
ArH), 6.76 (d, J = 7.8 Hz, 1H, CH2), 5.85 (s, 1H, CH2), 5.44 (s, 1H, CH2),
3.21 (d, J = 17.4 Hz, 1H, CH2), 2.99 (d, J = 17.4 Hz, 1H, CH2); 13C NMR
(75 MHz, DMSO-d6) 176.0 (C), 169.5 (C), 143.1 (C), 139.0 (C), 134.0
(C), 129.8 (CH), 129.7 (CH), 128.3 (CH), 126.6 (CH), 124.2 (CH), 123.6
(CH), 115.2 (CH2), 109.2 (CH), 60.5 (C), 37.6 (CH2). Anal. Calcd for
C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.40; H, 4.85; N, 9.75.
Synthesis and characterization of 3c: According to the above synthetic
procedure, 6c was obtained from 2g (106 mg, 0.260 mmol) in 93% yield
(100 mg, 0.241 mmol) as
a white solid. Rf = 0.35 (silica gel,
hexane/EtOAc = 2/1); m.p. 55–57 °C; IR (KBr) 2983 (C-H), 1802 (C=O),
1791 (C=O), 1777 (C=O), 1735 (C=O), 1719 (C=O), 1609 (C=C) cm-1; 1H
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10.1002/ejoc.201800084
European Journal of Organic Chemistry
FULL PAPER
NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 1H, ArH), 7.43-7.37 (m, 1H,
ArH), 7.22-7.19 (m, 2H, ArH), 6.39 (t, J = 2.7 Hz, 1H, CH2), 5.61 (t, J =
2.7 Hz, 1H, CH2), 3.19 (td, J = 2.7, 17.1 Hz, 1H, CH2), 2.81 (td, J = 2.7,
17.1 Hz, 1H, CH2), 1.65 (s, 9H, CH3), 1.20 (s, 9H, CH3); 13C NMR (75
MHz, CDCl3) 173.6 (C), 165.9 (C), 148.8 (C), 147.9 (C), 139.1 (C),
135.2 (C), 129.9 (CH), 129.0 (C), 125.2 (CH), 121.7 (CH), 121.4 (CH2),
115.3 (CH), 84.8 (C), 84.5 (C), 64.0 (C), 37.1 (CH2), 28.0 (CH3), 27.2
(CH3). Anal. Calcd for C22H26N2O6: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.81; H, 6.27; N, 6.66.
[9]
a) B. M. Trost, M. U. Frederiksen, Angew. Chem. Int. Ed. 2005, 44,
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In this procedure, 3c was obtained from 6c (62.2 mg, 0.150 mmol) in
98% yield (31.4 mg, 0.147 mmol) as a white solid. Rf = 0.16 (silica gel,
hexane/EtOAc = 1/3); m.p. 235–237 °C; IR (KBr) 3288 (N-H), 3222 (N-H),
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6098.
1
3062 (C-H), 3029 (C-H), 1725 (C=O), 1704 (C=O), 1662 (C=C) cm-1; H
NMR (300 MHz, CD3OD) δ 7.32-7.25 (m, 2H, ArH), 7.07 (dt, J = 0.9, 7.5
Hz, 1H, ArH), 6.94 (d, J = 0.9, 7.5 Hz, 1H, ArH), 6.02 (t, J = 2.7 Hz, 1H,
CH2), 5.52 (t, J = 2.7 Hz, 1H, CH2), 3.15 (td, J = 2.7, 17.1 Hz, 1H, CH2),
2.98 (td, J = 2.7, 17.1 Hz, 1H, CH2); 13C NMR (75 MHz, CD3OD) 180.5
(C), 172.9 (C), 142.7 (C), 140.0 (C), 131.8 (C), 131.1 (CH), 124.8 (CH),
124.3 (CH), 117.1 (CH2), 111.5 (CH), 62.9 (C), 39.0 (CH2). Anal. Calcd
for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.14; H, 4.81; N,
12.90.
[12] T. Emura, T. Esaki, K. Tachibana, M. Shimizu, J. Org. Chem. 2006, 71,
8559-8564.
[13] Here, one can see that the palladium catalyst would react with 5a to
provide π-allylpalladium intermediate and tert-butoxide anion with
concomitant loss of carbon dioxide. Then, oxindole anion generated by
deprotonation from 4a with tert-butoxide anion would attack to the
intermediate to afford 2a, accompanied by the regeneration of the
palladium catalyst. A similar reaction mechanism has been proposed in
Ref. 9e.
Acknowledgements
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3336-3338.
[15] S. Jayakumar, S. Muthusamy, M. Prakash, V. Kesavan, Eur. J. Org.
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This work was supported financially in part by JSPS Kakenhi
Grant number JP15K21046 and JP17K05858 from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
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Keywords: α-methylene-γ-butyrolactam • electrophilic amide
allylation • 3-heterosubstituted oxindoles • palladium catalyzed
reaction • spirocyclic oxindole
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E, T. Yuan, L. Yin, Y. Xu, Tetrahedron Lett. 2017, 58, 2521-2524; j) H.
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[19] In this process, the secondary amide group of 2 was activated as an
imide group by chemoselective protection using Boc2O. The resulting
Boc-protected derivatives were spontaneously cyclized through the
nucleophilic attack of nitrogen atom at the C3 position to the activated
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Entry for the Table of Contents
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Electrophilic amide allylation
Tetsuya Sengoku, Daichi Hayashi,
Masaki Takahashi and Hidemi Yoda*
Page No. – Page No.
Electrophilic amide allylation of 3-
heterosubstituted oxindoles: a new
route to spirocyclic 2-oxindole
containing α-methylene-γ-
A new route to access spirocyclic 2-oxindole containing α-methylene-γ-
butyrolactam structure via “electrophilic amide allylation” is reported. The key
reaction was accomplished by using acetoxy methacrylamides and
tetrakis(triphenylphosphine)palladium as a catalyst, affording a variety of the amide
allylated products in excellent yields.
butyrolactam structure
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